EP0447324B1 - Dérivés de pyrimidinedione-2,4 et médicaments les contenant - Google Patents

Dérivés de pyrimidinedione-2,4 et médicaments les contenant Download PDF

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Publication number
EP0447324B1
EP0447324B1 EP91400699A EP91400699A EP0447324B1 EP 0447324 B1 EP0447324 B1 EP 0447324B1 EP 91400699 A EP91400699 A EP 91400699A EP 91400699 A EP91400699 A EP 91400699A EP 0447324 B1 EP0447324 B1 EP 0447324B1
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EP
European Patent Office
Prior art keywords
formula
compound
denotes
alkyl
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP91400699A
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German (de)
English (en)
French (fr)
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EP0447324A1 (fr
Inventor
Laurent Fraisse
Gérard Le Fur
Jean-Baptiste Verlhac
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi-Synthelabo Nationale Elf Aquitaine Ste
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Societe National Elf Aquitaine
Sanofi SA
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Definitions

  • the present invention relates to derivatives of pyrimidinedione-2,4 and the medicaments containing them.
  • These compounds in particular exhibit anti-radical activity and are inhibitors of the peroxidation of lipids of biological membranes.
  • uric acid and some of its N-methylated derivatives scavenge free radicals in vitro and it has been considered in Pro. Natl. Acad. Sci. USA 78 6858 (1981) that uric acid could play a protective role in humans against the toxicity of oxygen radicals.
  • uric acid is only active on some of these reactive species since it does not inhibit the peroxidation of membrane lipids, unlike the compounds of the present invention.
  • FR-A-2 232 320 describes amino uracils with cholesterol-lowering properties that do not contain a long-chain alkyl substituent.
  • Chem. Abs. Flight. 112 (17), (1990), 688 no. 157937 describes the use of derivatives of uric acid, close to the compounds of the invention for the purpose of studying host-receptor interactions.
  • EP-A-0 092 398 relates to 8-phenylxanthines prepared from 5,6-diaminouracils close to the compounds of the invention but containing no long chain alkyl substituent.
  • FR-A-2 531 085 likewise illustrates the preparation of xanthine derivatives from 5,6-diaminouracils which also do not have long chain alkyl groups.
  • US-A-2,781,344 proposes 4,5-diaminouracil derivatives as intermediates for the synthesis of purine derivatives.
  • the compounds of the invention correspond to the formula in which R1 represents H or (C7-C20) alkyl, R2 represents H or (C7-C20) alkyl, R3 represents H, CH3 or (C7-C20) alkyl, R4 represents H, CH3 or (C7-C20) alkyl, Z1 and Z2 each represent H or together represent the carbonyl or thiocarbonyl group, it being understood that only one of the substituents R1 to R4 represents a (C7-C20) alkyl group and that one of the R3 or R4 is different from H when R1 represents n-dodecyl, as well as the addition salts of these compounds with pharmaceutically acceptable mineral and organic acids.
  • Formamide (IV) is obtained, for example, by the action of zinc or alkaline dithionite and formic acid.
  • R1 represents H
  • the compounds of formula II in which R1 represents H can also be prepared from 6-chloro-pyrimidinedione-2,4 according to the reaction scheme (b) by applying conventional methods, such as that described in Liebigs Ann. Chem. 677 p. 113 (1964).
  • the compounds of formula II in which R1 is a (C7-C20) alkyl group are prepared by the action of the amine R1NH2 on the brominated derivative of formula VI in which R2, R3 and R4 are as in formula I.
  • the derivative (VI) is obtained by the action of bromine in acetic acid or of N-bromo succinimide in a mixture of acetic acid and anhydride on the compound (V), as described in Liebigs Ann. Chem. p. 1847-54 (1979); when R3 represents H, it is preferable, before carrying out the bromination, to protect the nitrogen, for example with a benzyl group, which will be eliminated by catalytic hydrogenation after the reaction with R1NH2.
  • R1 represents a (C7-C20) alkyl group
  • it is necessary to block the nitrogen carrying R3 and the reaction scheme is as follows:
  • a polar solvent such as an alcohol
  • R2, H and R3 or R3, identical or different, represent H or CH3 .
  • the compound of formula V bis is treated, in basic medium, with a compound R4X in which X represents a halogen atom or when R4 represents CH3 preferably by (CH3) 2SO4.
  • the salts of the compounds of formula I which carry amine functions are prepared by the action of at least one equivalent of the acid on the amine in solution, they are isolated by precipitation or by evaporation of the solvent and purified by recrystallization if takes place.
  • compositions and medicaments having as active principle at least one of the compounds of formula I, in which R1 represents H or (C7-C20) alkyl, R2 represents H or (C7-C20) alkyl, R3 represents H, CH3 or (C7-C20) alkyl, R4 represents H, CH3 or (C7-C20) alkyl, Z1 and Z2 each represent H or together represent the carbonyl or thiocarbonyl group, it being understood that only one of the substituents R1 to R4 represents a (C7-C20) alkyl group and that one of the R3 or R4 is different from H when R1 represents n-dodecyl, or one of the salts with a pharmaceutically acceptable acid, are another object of the invention; particularly preferred are the compounds in which one of the symbols R1, R2, R3 or R4 represents a C12 or C20 alkyl group.
  • the anti-radical action of an XH product is commonly determined, in vitro, by measuring the neutralization of the 1,1-diphenyl, 2-picryl-hydrazyl (DPPH ⁇ ) radical, stable at 20 ° C., by the product.
  • DPPH ⁇ 1,1-diphenyl, 2-picryl-hydrazyl
  • the compounds of the invention are, in this test, active at doses comparable to those of uric acid.
  • compositions according to the invention comprising as active principle at least one of the compounds of formula I or one of its salts with a pharmaceutically acceptable acid will be administered for the preventive or curative treatment of degenerative phenomena linked to the presence of radicals free, oral, parenteral, transmucosal or percutaneous.
  • the unit and daily doses will depend on the compound, the nature and severity of the disease, the weight and condition of the subject and the route of administration; in general, orally the unit dose will be in adults from 1 mg to 500 mg, while intravenously, it will be 0.1 to 25 mg.
  • the compounds of formula I and their salts with pharmaceutically acceptable acids also find application in cosmetic compositions to counter aging of the skin.
  • the medium is maintained at its reflux temperature for 7 hours, then, after returning to ambient temperature, a concentrated aqueous solution of HCl is brought to an acid pH and then 200 ml of water.
  • the precipitate formed is isolated by filtration and then recrystallized from ethanol. 29 g of the sought product are thus isolated, which melts at more than 250 ° C.
  • the anti-free radical activity of these compounds was determined as follows: 970% of a mixture of methanol and of aqueous solution buffered with TRIS (tromethamine), HCl (10 mM-pH 7.4) are introduced into at the rate of 1 volume of methanol per 2 of buffer, 20 "l of a solution of DPPH ⁇ 1mM and 10" l of a solution of the product to be tested in dimethyl sulfoxide. The mixture is maintained for 20 minutes at 20 ° C. before determining the optical density at 517 nm relative to a control mixture for which the product to be tested has not been introduced into dimethylsulfoxide.
  • the percentage P of trapping of the free radical is defined as a ratio of the optical densities D
  • Table 5 shows the CE50 for compounds according to the invention, as well as for uric acid and its N-methylated derivatives and for product A.
  • PRODUCT CE50 (»M) PRODUCT CE50 (»M) Uric acid 4.5 example 10 5.2 Uric acid CH3-1 4.5 11 6.2 CH3-3 3.2 12 4.5 CH3-7 20 13 3.2 CH3-9 5.2 AT 4 14 4 example 1 5 15 3.4 2 7 3 5.5 4 6.4 16 6.2 5 6.4 6 5.6 7 6.5 8 2.7 9 6.5
  • the inhibitory activity of the peroxidation of the membrane lipids of the compounds was determined as follows:
  • a beef heart is taken immediately after the slaughter of the animal and cooled to 4 ° C, temperature at which all the following operations will be carried out.
  • the heart is washed with an aqueous buffer solution at pH 7.4 (TRIS, 10 mM HCl, 2 mM EDTA, 20 mM KCl, 250 mM sucrose) then the connective tissues and fats are eliminated.
  • the muscle is then chopped and the mince is suspended in an aqueous buffer solution at pH 7.4 (TRIS, 10 mM HCl, 250 mM sucrose, 1 mM EDTA) at the rate of 700 g of muscle per 3 liters.
  • the pH of the suspension is readjusted to 7.4, regularly, before isolating the mince by filtration through a gauze.
  • a fraction of thawed mitochondria is dispersed at 4 ° C. in a buffered aqueous solution of pH 7.4 (TRIS, 30 mM HCl containing 140 mM KCl), to obtain a protein concentration of 0.37 mg / ml; 960 "l of this suspension are charged with 10" l of a 100 mM dihydroxyfumaric acid solution, the pH of which has been adjusted to pH 7.42 "l of a solution of the product to be tested in solution in dimethyl sulfoxide ( DMSO) and 30 »l of a solution of FeSO4, (NH4) 2SO4 1mM, kept away from oxygen and light.
  • the control sample contains DMSO without the product to be tested while the blank contains neither dihydroxyfumaric acid nor iron.
  • Each sample is immediately introduced into 1.5 ml of a solution of trichloroacetic acid 13.5% (w / v) and of thiobarbituric acid 0.33% (w / v) in an aqueous solution of hydrochloric acid 0 , 85 N and the containers are closed and then brought to 100 ° C for 15 minutes, before being cooled to room temperature in 5 minutes. 1 ml of an aqueous solution of 70% (w / v) trichloroacetic acid is then added before carrying out the spectrofluorimetric measurement, with an excitation wavelength of 515 nm and an emission wavelength of 553 nm.
  • a standard range of bis- (diethylacetal) malonaldehyde diluted in an aqueous 0.1 N HCl solution makes it possible to calculate to which aldehyde concentration corresponds to each intensity of fluorescence i.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Toxicology (AREA)
  • Vascular Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Transplantation (AREA)
  • Hospice & Palliative Care (AREA)
  • Biochemistry (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP91400699A 1990-03-15 1991-03-14 Dérivés de pyrimidinedione-2,4 et médicaments les contenant Expired - Lifetime EP0447324B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9003342 1990-03-15
FR909003342A FR2659656B1 (fr) 1990-03-15 1990-03-15 Derives de pyrimidinedione-2,4 et medicaments les contenant.

Publications (2)

Publication Number Publication Date
EP0447324A1 EP0447324A1 (fr) 1991-09-18
EP0447324B1 true EP0447324B1 (fr) 1995-12-20

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EP91400699A Expired - Lifetime EP0447324B1 (fr) 1990-03-15 1991-03-14 Dérivés de pyrimidinedione-2,4 et médicaments les contenant

Country Status (11)

Country Link
EP (1) EP0447324B1 (pt)
JP (1) JP2983669B2 (pt)
AT (1) ATE131817T1 (pt)
CA (1) CA2038198A1 (pt)
DE (1) DE69115526T2 (pt)
DK (1) DK0447324T3 (pt)
ES (1) ES2081446T3 (pt)
FR (1) FR2659656B1 (pt)
GR (1) GR3019123T3 (pt)
IE (1) IE71192B1 (pt)
PT (1) PT97035B (pt)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU214331B (hu) * 1992-06-17 1998-03-02 Gyógyszerkutató Intézet Kft. Eljárás piperazin- és homopiperazinszármazékok és ezeket tartalmazó gyógyszerkészítmények előállítására
US5889013A (en) * 1994-02-28 1999-03-30 Sunkyong Industries Co., Inc. Pyrimidine acyclonucleoside derivatives
JP3497554B2 (ja) * 1994-03-25 2004-02-16 日本臓器製薬株式会社 新規プリン誘導体及びその薬学的に許容される塩
DE19702785A1 (de) * 1997-01-27 1998-07-30 Bayer Ag Neue cyclische Harnstoffderivate
US6417180B1 (en) * 1998-10-07 2002-07-09 University Of Massachusetts Zinc finger-reactive antimicrobial compounds
SE9903544D0 (sv) 1999-10-01 1999-10-01 Astra Pharma Prod Novel compounds
GB2359081A (en) 2000-02-11 2001-08-15 Astrazeneca Uk Ltd Pharmaceutically active thiazolopyrimidines
GB2359078A (en) 2000-02-11 2001-08-15 Astrazeneca Uk Ltd Pharmaceutically active pyrimidine derivatives
GB2359551A (en) 2000-02-23 2001-08-29 Astrazeneca Uk Ltd Pharmaceutically active pyrimidine derivatives
SE0003828D0 (sv) 2000-10-20 2000-10-20 Astrazeneca Ab Novel compounds
SE0101322D0 (sv) 2001-04-12 2001-04-12 Astrazeneca Ab Novel compounds
GB0221828D0 (en) 2002-09-20 2002-10-30 Astrazeneca Ab Novel compound
GB0328243D0 (en) 2003-12-05 2004-01-07 Astrazeneca Ab Methods
JP2010501590A (ja) * 2006-08-23 2010-01-21 アメリカ合衆国 酸化的ストレス関連疾患の治療または予防方法
WO2014205234A1 (en) * 2013-06-21 2014-12-24 MyoKardia, Inc. Cycloalkyl-substituted pyrimidinedione compounds
SMT202000071T1 (it) 2013-06-21 2020-03-13 Myokardia Inc Composti di pirimidinadione contro le condizioni cardiache
CN108912121A (zh) * 2018-08-08 2018-11-30 南京纽邦生物科技有限公司 三种甲基尿酸类化合物的制备方法、中间体及中间体的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2781344A (en) * 1953-05-04 1957-02-12 Monsanto Chemicals Formylation of amino-pyrimidines
DE2329399A1 (de) * 1973-06-08 1975-01-02 Wuelfing J A Fa 4-alkyl-aminouracile, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
US4452788A (en) * 1982-04-21 1984-06-05 Warner-Lambert Company Substituted 8-phenylxanthines
FR2531085A1 (fr) * 1982-07-28 1984-02-03 Adir Nouveaux derives de la xanthine, leur procede de preparation et les compositions pharmaceutiques les renfermant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Pro. Natl. Acad. Sci. USA 78(1981), 6858 *

Also Published As

Publication number Publication date
PT97035B (pt) 1998-07-31
JP2983669B2 (ja) 1999-11-29
IE910853A1 (en) 1991-09-25
FR2659656B1 (fr) 1994-09-09
EP0447324A1 (fr) 1991-09-18
ATE131817T1 (de) 1996-01-15
DE69115526T2 (de) 1996-06-05
PT97035A (pt) 1991-10-31
CA2038198A1 (en) 1991-09-16
ES2081446T3 (es) 1996-03-16
DE69115526D1 (de) 1996-02-01
FR2659656A1 (fr) 1991-09-20
IE71192B1 (en) 1997-02-12
DK0447324T3 (da) 1996-04-29
JPH04217672A (ja) 1992-08-07
GR3019123T3 (en) 1996-05-31

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